1. TRANSDERMAL DRUG DELIVERY
SYSTEMS
ROHIT GOYAL
M.PHARMACY
SECTION-2

2. 2
Transdermal Drug Delivery system
CONTENTS
Introduction
A brief review of skin structure
Pathway of transdermal permeation
Types of transdermal patches
Penetration enhancers
Products in the market

3. DEFINITION:-
• These systems are used when our aim is to deliver drugs
through skin in a predetermined controlled fashion the
result is transdermal drug delivery.
• ADVANTAGES:-
• 1.Avoidence of risks and inconveniences of I.V therapy.
• 2.Reduce side effects due to optimization of the blood
concentration time profile.

4. MORE ADVANTAGES:-
• Drugs with very short half life. eg is NITROGLYCERIN
when administered as transdermal patch release
medicament at constant rate for a time period more than
that obtainable with oral formulations.
• First pass metabolism in the liver and GI tract is avoided.
• Drugs with narrow therapeutic indices can be safely
administered since better control of release is possible.
• Reduced need for active administration (some patches can
last 7 days).
• The patch is noninvasive and dosage can be stopped by
removal.
• Easy to apply and to monitor.

5. DISADVANTAGES:-
1.Drug dose is large.
2.Drug has large molecular size.
3.Drug is metabolized in skin.
4.Drug is highly lipophilic and hydrophilic
5.Drug undergoes degradation in skin.
6.Drug is skin sensitizing and irritating.

6. A brief review of skin structure

7. STRUCTURE AND FUNCTION OF HUMAN SKIN
Human skin is the largest organ of the human body providing around
10% of the body mass of an average person and it covers an average
area of 1.7m2. Whilst such a large and easily accessible organ
apparently offers ideal and multiple sites to administer therapeutic
agents for both local and systemic actions, human skin is a highly
efficient self-repairing barrier designed to keep ‘the insides in and the
outside out.’
The human skin consists of-
1.EPIDERMIS—
*Stratum corneum
*Stratum germinativum
* Stratum spinosum
* Stratum granulosum
* Stratum lucidum
 2. Dermis-The Dermis consists of two sub-layers:
* The Papillary dermis and
* The Reticular dermis

8. The skin can be considered to have
four distinct layers of tissue
1. Non-viable epidermis (stratum corneum)
2. Viable epidermis
3. Viable dermis
4. Subcutaneous connective tissue (hypodermis)

9.  Stratum Corneum:
stratum corneum comprises only around 10 µm thick when dry,
although it may swell to several times this thickness when wet
 stratum corneum serves to regulate water loss from the body whilst
preventing the entry of harmful materials including microorganisms
The barrier nature of the stratum corneum depends critically on its
unique constituents; 75-80% is protein, 5-15% is lipid with 5-10%

10. The stratum corneum is the outermost layer of the epidermis and is composed
mainly of dead cells that lack nuclei.
These are sloughed off during the day and replaced by new cells from the
stratum germinativum.
There is a high proportion of keratin, an insoluble protein, with a high proportion
of disulfide bridges (from cysteine), and also a high level of glycine and alanine
residues that allow strong H-bonds to neighbouring amino acids.

11.  Stratum germinativum:
deepest layer of the epidermis
 new cells are generated for the renewal of the epidermal layers of the
skin.
mitotic division is responsible for the generation of the new epidermal
skin cells.
A newly formed cell will undergo a progressive maturation called
keratinisation as it migrates to the surface of the skin

12.  Stratum spinosum:
The stratum spinosum (also known as the spinous layer or prickle cell
layer) is found on top of the basal layer.
Stratum spinosumlayer consists of two to six rows of keratinocytes.
 Stratum granulosum:
one to three cell layers thick the stratum granulosum contains enzymes
that begin degradation of the viable cell components such as the nuclei
and organelles. The granular cells are so called because they acquire
granular structures

13. DERMIS:
The dermis is typically 3-5 mm thick and is the major component
of human skin. It is composed of a network of connective tissue
predominantly collagen fibrils providing support and elastic
tissue providing flexibility
 Subcutaneous Fat Layer:
The subcutaneous fat layer bridges between the overlying dermis
and the underlying body constituents
This layer of adipose tissue principally serves to insulate the body
and to provide mechanical protection against physical shock

14. What kind of drugs can be
incorporated into a patch?
Compounds with low logP[partition coeff.] will not
diffuse into skin lipids
However, compounds with high logP also have
difficulties, this time associated with their diffusion
out of the stratum corneum.
The accepted range of logP values is between 1 and 3.

15. Table 2.5- List of Selected Prescription Transdermal
Products
 DRUG NAME EXAMPLES OF BRAND NAME
 Fentanyl Duragesic
Clonidine catapres TTS
Nicotine Nicoderm CQ, Nicotrol
Nitroglycerine Nitro-Dur, Deponit
 Testosterone Testoderm TTS
 Estradiol Climara,Combipatch
 Scopolamine Transderm scop
 Oxybutynin Awaiting FDA approval
 Methylphenidate Awaiting FDA approval

16. Types of transdermal drug delivery systems
1.Monolithic(matrix)systems
2.Reservior(membrane)systems
3.Monolithic-reservior systems
4.Microreservior type systems
5.Drug in adhesive type systems

17. IMPORTANT NOTE:-
• The choice of these systems for controlling drug release
depends upon the major rate limiting step in the
absorption of drug from such devices.The two rate-
limiting steps are:-
• 1.Rate of drug diffusion from the device R
• 2.Rate of drug permeation through the stratum corneum
R’
• The overall rate of drug transport is proportional to the
sum(R+R’).

18. 1.Monolithic(matrix)systems:-
These systems are used when R’ is the rate –controlling step(R’<R)
and drug has a large therapeutic index so that overdosing does not
precipitate toxic reactions.The categories of matrix devices are-one in
which drug is dissolved(below saturation levels) in the polymer
matrix and other in which the drug is dispersed(much above
saturation levels).

19. 2.Reservior(membrane)systems:-
These are used when drug permeation rate is rapid and absoption
should therefore by controlled by controlling drug realease(R<R’).It is
suitable for potent drugs with low therapeutic indices where
monitoring drug levels in a narrow range is essential.

20. 3.Monolithic-reservior systems:-
It is basically a device having drug release kinetics intermediate
between monolithic and reservior systems.Here the drug-polymer
matrix is layered by a rate-controlling membrane.Release is controlled
by diffusion of drug through a thicker layer of polymer matrix.

21. Micro reservoir type transdermal
patch(s):

22.  The drug reservoir is formed by suspending the drug solids
in an aqueous solution of water miscible drug solubilizer
e.g. polyethylene glycol. The drug suspension is
homogenously dispersed by a high shear mechanical force
in lipophillic polymer, forming thousands of unleachable
microscopic drug reservoirs (micro reservoirs). The
dispersion is quickly stabilized by immediately cross linking
the polymer chains in-situ which produces a medicated
polymer disc of a specific area and fixed thickness.
Occlusive base plate mounted between the medicated disc
and adhesive form backing prevents the loss of drug
through the backing membrane. This system is exemplified
by development of Nitrodisc®.

23. 4.Drug in adhesive type transdermal patch

24. LIMITATIONS:-
A major limitation of transdermal drug delivery system is poor skin
penetrability of several drugs.This problem can be overcome by use of
penetration enhancers such as
1.GLYCEROL
2.PROPYLENE GLYCOL
3.SODIUM LAURYL SULPHATE
4.DIMETHYL SULPHOXIDE.

25. Some transdermal delivery systems available in
market:-
Transdermal drug delivery Purpose
System
MATRIX :-
1.Nitro-Dur In angina pectoris for 1 day
RESERVIOR:-
1.Transderm Nitro In angina attack for 1 day
2.Catapress TTS In Hypertension for 1 week
MATRIX-RESERVIOR:-
1.Nitrodisc Transdermal administration for 1 day

26. NOVEL METHODS IN
TOPICAL/TRANSDERMAL DRUG DELIVERY
New dosage forms and drug delivery systems providing excellent
improvement in drug therapy are termed as novel drug delivery
systems. These are termed novel, due to recent development with
satisfactory results in the field of drug delivery (Juliano et al., 1980).
Some of these novel advanced transdermal technologies include
(Prausnitz & Allen, 1998):
• Penetration enhancers
• Iontophoresis
• Electroporation and sonophoresis
• Microfabricated microneedles and microchips
• Vesicular approaches

27. PENETRATION ENHANCING TECHNIQUES

28. 1.Chemical permeation enhancers:-
A substance that will increase the permeability of the epithelial barrier
by modifying its structure also termed as accelerants or sorption
promoters-can enhance drug flux.
Ideal Penetration Enhancer:-
1.Non-toxic, non-irritating, non-allergenic.
2.Immediate onset of increased permeability.
3.Immediate recovery of normal barrier properties upon
removed(reversible).
4.Physically and Chemically compatible with a wide
range of drugs.

29. Permeation enhancers used for TDDS
CategoryCategory ExampleExample
SolventsSolvents
Anionic surfactantsAnionic surfactants
NonionicNonionic
surfactantssurfactants
Essential oilsEssential oils
MethanolMethanol
EthanolEthanol
Dimethyl sulfoxideDimethyl sulfoxide
Propylene glycolPropylene glycol
2- Pyrrolidone2- Pyrrolidone
Isopropyl myristateIsopropyl myristate
LaurocapramLaurocapram
Sodium lauryl sulfateSodium lauryl sulfate
Sorbitan monolaurateSorbitan monolaurate
PluronicPluronic
Cardamom oilCardamom oil
Caraway oil, LemonCaraway oil, Lemon
oiloil

30. 2.Iontophoresis:-
 The electrical driving of charged molecules into tissue, passes a small
direct current (approximately 0.5 mA/cm2
) through a drug containing
electrode in contact with the skin. The most popular electrodes are
based on the silver/silver chloride redox couple.
Three main mechanisms enhance molecular transport:
 Charged species are driven primarily by electrical repulsion from the
driving electrode.
 Flow of electric current may increase the permeability of skin and
 Electro-osmosis may affect uncharged molecules and large polar
peptides.
 Limitations: Hair follicle damage is possible.

31. The basic principle of iontophoresis is that a small electric current is
applied to the skin. This provides the driving force to primarily enable
penetration of charged molecules into the skin. A drug reservoir is
placed on the skin under the active electrode with the same charge as
the penetrant. A indifferent counter electrode is positioned elsewhere on
the body. The active electrode effectively repels the active substance and
forces it into the skin . This simple electrorepulsion is known as the main
mechanism responsible for penetration enhancement by iontophoresis.
The number of charged molecules which are moved across the barrier
correlates directly to the applied current and thus can be controlled by
the current density. Other factors include the possibility to increase the
permeability of the skin barrier in the presence of a flow of electric
current and electroosmosis. Electroosmosis results when an electric field
is applied to a charged membrane such as the skin and causes a solvent
flow across this membrane. This stream of solvent carries along with it
dissolved molecules. It enhances the penetration of neutral and
especially polar substances

32. Iontophoresis

33. Iontophoretic Patches

34. Drawbacks of Iontophoresis:-
Inspite of its extensive application the drawbacks associated with the technology include the possibility of electric shock, skin
irritation, burns and cost of treatment. Recent efforts in this technology have resulted in the design of iontophoretic electrodes,
which avoids burns. The technique has gained acceptance for local therapy. Its application for systemic medication will require
furtherresearchtoelucidatesimplemeansofdrugdelivery

35. 3. Electroporation:-
The drawbacks associated with chemical enhancers and iontophoresis can
be overcome to a certain extent by electroporation technology developed
in recent years. This technology has been developed to overcome the most
daunting challenges of transdermal drug delivery. The process involves the
application of transient high voltage electrical pulse to cause rapid
dissociation of the stratum corneum through which large and small
peptides, oligonucleotides and other drugs can pass in significant
amounts . The degree of enhancement achieved in vitro is related to the
applied voltage, number and duration of the pulses offering the possibility
of a controllable phenomenon.

36. • Skin electroporation (electropermeabilization) creates transient aqueous pores in the
lipid by application of high voltage of electrical pulses of approximately 100–1000
V/Cm for short time(milliseconds). These pores provide pathways for drug penetration
that travel straight through the horny layer.

37. Electroporation

38. Sonophoresis:-
Another technique besides electroporation attempting to overcome
the challenges of transdermal drug delivery involves the usage of high
frequency ultrasound waves. The application of low frequency
ultrasound was shown to increase the permeability of human skin to
many drugs including high molecular weight proteins by several
orders of magnitude thus making transdermal administration of these
molecules potentially feasible. Low-frequency ultrasound is thus
potential non-invasive technology for transdermal drug delivery.
Despite the excitement these findings have provoked it is necessary to
maintain an appropriate perspective until several basic questions are
answered with respect to mechanism

39. Sonophoresis

40. MICRONEEDLES

41.  Microneedles are needles that are 10 to 200 µm in height
and 10 to 50 µm in width They are solid or hollow and are
connected to a reservoir which contains the active
principle.
Needles of approximately with or without centre hollow
channels are placed onto the skin surface so that they
penetrate the stratum corneum and epidermis without
reaching the nerve endings present in the upper dermis.

42. Microneedle arrays are applied to the skin surface so
that they pierce the upper epidermis far enough to
increase skin permeability and allow drug delivery, but
too short to cause any pain to the receptors in the
dermis. Therefore there is no limitation concerning
polarity and molecular weight of the delivered
molecules.

43. Products in the market:-
1.Clonidine
Works as an agonist of adrenaline at
the presynaptic α2 adrenergic
Product name = Catapres-TTS®
used to treat hypertension

44. 2.Ethinylestradiol(EO)and Norelgestromin(N)
Product name = Ortho-Evra®
Used for Contraception
Type of patch = Drug-in-Adhesive
Frequency of application = weekly

45. 45
3.Lidocaine
 Product Name = Lidoderm®
 Used for: analgesia of postheretic neuralgia (PHN), a painful condition caused
by the varicella zoster virus (herpes zoster = shingles)
 Type of Patch = Reservoir
 Frequency of Application = Daily

46. 46
4.Nicotine
Product name = Habitrol®
, Nicoderm – CQ®
, Nicotrol®
, Prostep®
Used for: Smoking cessation
Frequency of administration = Daily

47. 47
5.Nitroglycerin
Works by producing nitric oxide (NO), which then acts as a
vasodilator
Product Names = Nitro-Dur®
, Transderm-Nitro®
Used for: Angina
Type of Patch = Nitro-Dur is Drug-in-adhesive
Nitrodisc is reservoir
Frequency of administration = Daily

48. 48
6.Estradiol
Product Name = Alora®
, Climara®
, Esclim®
, Estraderm®
, FemPatch®
,
Vivelle®
, Vivelle-DOT®
Used for: Hormone replacement
Type of Patch: Drug-in-adhesive
Frequency of application = weekly

49. 49
7.Estradiol + Norethindrone
Product name = CombiPatch®
Used for: Hormone Replacement

50. 50
8.Oxybutynin
Works as competitive antagonist of the muscarinic acetycholine
receptor
Product name = Oxytrol®
Used for: Overactive bladder (antispasmodic)
Type of Patch: Drug-in-adhesive
Frequency of application = twice a week

51. 51
9.Scopolamine
Works as competitive antagonist of acetylcholine at the muscarinic
receptor
Product Name = Transderm Scop®
Used for: Motion Sickness

52. 52
10.Lidocaine + Epinephrine
Product name = Lidosite
Used for: Dermal anesthesia
Type of Patch = Reservoir, iontophoretic.
Epinephrine acts as vasoconstrictor, thus prolonging the duration of action of
lidocaine (by delaying resorption) at the site

53. 53
11.Testosterone
Product Names = Androderm®
, Testoderm TTS®
, Testoderm®
Used for: Hypogonadism

54. Currently available medications for transdermal delivery
DrugDrug
TradeTrade
namename
Type ofType of
transdermaltransdermal
patchpatch
ManufacturerManufacturer IndicationIndication
FentanylFentanyl DuragesicDuragesic ReservoirReservoir Alza / JanssenAlza / Janssen
PharmaceuticaPharmaceutica
Moderate/ Severe painModerate/ Severe pain
NitroglyceNitroglyce
rinerine
DeponitDeponit
MinitranMinitran
NitrodiscNitrodisc
NitrodurNitrodur
TransdermTransderm
NitroNitro
Drug inDrug in
adhesiveadhesive
Drug inDrug in
adhesiveadhesive
MicroMicro
reservoirreservoir
MatrixMatrix
ReservoirReservoir
Schwarz PharmaSchwarz Pharma
3M Pharmaceuticals3M Pharmaceuticals
Searle, USASearle, USA
Key PharmaceuticalsKey Pharmaceuticals
Alza/NovartisAlza/Novartis
Angina PectorisAngina Pectoris
NicotineNicotine ProstepProstep
NicotrolNicotrol
HabitraolHabitraol
ReservoirReservoir
Drug inDrug in
adhesiveadhesive
Drug inDrug in
adhesiveadhesive
ElanCorp/Lederie LabsElanCorp/Lederie Labs
Cygnus Inc./McNeilCygnus Inc./McNeil
Consumer ProductsConsumer Products
Ltd.Ltd.
NovartisNovartis
Smoking CessationSmoking Cessation

55. TestosteroneTestosterone AndrodermAndroderm
Testoderm TTSTestoderm TTS
ReservoirReservoir
ReservoirReservoir
Thera Tech/Thera Tech/
GlaxoSmithKlineGlaxoSmithKline
AlzaAlza
HypogonadismHypogonadism
in malesin males
ClonidineClonidine Catapres-TTSCatapres-TTS Membrane matrixMembrane matrix
hybrid typehybrid type
Alza/BoehingerAlza/Boehinger
IngelheimIngelheim
HypertensionHypertension
LidocaineLidocaine LidodermLidoderm Drug in adhesiveDrug in adhesive Cerner Multum, Inc.Cerner Multum, Inc. AnestheticAnesthetic
ScopolamineScopolamine Transderm ScopTransderm Scop Membrane matrixMembrane matrix
hybrid typehybrid type
Alza/NovartisAlza/Novartis Motion sicknessMotion sickness
EstradiolEstradiol
EthinylEthinyl
ClimaraClimara
VivelleVivelle
EstradermEstraderm
EsclimEsclim
Ortho EvraOrtho Evra
Drug in adhesiveDrug in adhesive
Drug in adhesiveDrug in adhesive
ReservoirReservoir
Drug in adhesiveDrug in adhesive
Drug in adhesiveDrug in adhesive
3M Pharmaceuticals/3M Pharmaceuticals/
Berlex LabsBerlex Labs
Noven Pharma/NovartisNoven Pharma/Novartis
Alza/NovartisAlza/Novartis
Women First Healthcare,Women First Healthcare,
Inc.Inc.
Johnson & JohnsonJohnson & Johnson
PostmenstrualPostmenstrual
SyndromeSyndrome

56. THANKS